Humans share a similar repertoire of genetic and cellular make-up with other vertebrates and invertebrates of much less complexity like the fruit fly Drosophila melanogaster. By applying the powerful genetics of Drosophila and biochemical and cell biological methodologies, our long term goal is to establish an animal system to study the problems of human neural degeneration so that the cause/effect of neural degeneration can be studied on the cellular level, as well as on the behavior level based on readout of the whole organism. Our current focus is to investigate how Presenilin (Psn) networks with other proteins for its functioning. Normally Presenilin is part of gamma-secretase complex that contains another three components, Nicastrin (Net), Aph-1, and Pen-2, to cleave transmembrane proteins including Notch and amyloid precursor protein (APP). One key event of achieving matured functional Presenilin is to have the full-length Psn undergoing endoproteolysis during assembly of the protease complex, so that the N-terminal and C-terminal halves of Psn can associate with each other and mature as a heterodimer, which then provides the catalytic activity for the protease. In this proposal, we intend to test whether constitutively expressing Psn forms that bypass endoproteolysis process can substitute for endogenous Psn throughout the animal life without compromise. We will investigate the impact(s) of Psn endoproteolysis on substrate recognition of gamma-secretase, and whether modified Psn forms result in compromised gamma-secretase activity in adults that is manifested in reduced lifespan or neural health (specific aim 1). The reagents here also allow investigation whether other components of the protease complex are required to regulate g-gamma-secretase activity in addition to their roles in assisting Psn maturation (specific aims 2 and 3). The proposed research here provides an in vivo system to study Psn functioning and gamma-secretase activity comprehensively; this system is economical for examining the impact of Presenilin and gamma- secretase activity on normal aging process. The information here will shed light on how a mutated Psn form in human result in compromised gamma-secretase activity in adults that is manifested in neurodegeneration like what occurs in patients with Alzheimer's disease. [unreadable] [unreadable] [unreadable]